Under the cases of anemia, trauma, tissue necrosis and defect, tissues or cells are often in a hypoxia state. Hypoxia leads to the transcriptional induction of a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, cell growth and proliferation. Wherein, hypoxia inducible factor (HIF) is a transcription factor activating in the case of oxygen reduction of somatic cell, and is widely distributed in various parts of the body, especially in endangium, heart, brain, kidney, liver, etc. HIF is a heterodimer containing an oxygen-regulated α-subunit (HIFα), and a constitutively expressed β-subunit (HIFβ/ARNT). In oxygenated (normoxic) cells, HIFα subunits are rapidly degraded by a mechanism that involves ubiquitination by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Under hypoxic conditions, HIFα is not degraded, and an active HIFα/β complex accumulates in the nucleus, and activates the expression of several genes including glycolytic enzymes, glucose transporters, erythropoietin (EPO), and vascular endothelial growth factor (VEGF).
Erythropoietin (EPO), a naturally occurring hormone that is produced in response to HIFα, stimulates the production of red blood cells (erythrocytes), which carry oxygen throughout the body. EPO is normally secreted by the kidneys, and endogenous EPO is increased under conditions of reduced oxygen (hypoxia). All types of anemia are characterized by the blood's reduced capacity to carry oxygen, and thus are associated with similar signs and symptoms, including pallor of the skin and mucous membranes, weakness, dizziness, easy fatigability, and drowsiness, leading to a decrease in quality of life. Anemia is typically associated with a condition in which the blood is deficient in red blood cells or in hemoglobin. Common causes of anemia include deficiencies of iron, vitamin B12, and folic acid. Anemia can also develop in association with chronic diseases, e.g., inflammatory disorders, including disorders with consequent inflammatory suppression of marrow, etc. Anemia also associates with renal dysfunction, and most dialysis patients with renal failure often suffer from chronic anemia.
Prolyl hydroxylase domain (PHD) is a key factor regulating HIF. Under a constant oxygen condition, PHD can hydroxylate two key proline residue Pro402 and Pro564 of HIF alpha to increase its affinity with pVHL and accelerate the degradation process. Under hypoxia and other pathological conditions, PHD-catalyzed HIF reaction is blocked, and the speed of proteolytic degradation slows, which results in intracellular accumulation of HIF a, thereby causes a series of adaptive cellular response to hypoxia. Using PHD inhibitors to inhibit PHD and extend the action time of HIF, thereby to increase the expression of EPO and other genes, which can effectively treat and prevent HIF-related and/or EPO-related disorders, such as anemia, ischemic and hypoxic conditions.